Collagen is the major structural protein of human and animal connective tissues. It is widely accepted as a safe and natural biomaterial for the manufacture of a broad range of collagen-based food, cosmetic and medical products.
Collagen is commonly used in the construction of engineered bio-mimetic collagenous tissues for therapeutic applications. These bio-mimetic tissues are generally made from collagen gels produced from soluble monomeric collagen.
Collagen hydrogels formed from monomeric collagen may be readily seeded with cells. Collagen hydrogels with interstitially seeded (tissue relevant) cells have long been used in tissue engineering as cell compatible, simple, 3D models of living tissues. However, the gels rely on the fibrillogenesis (gelling) of collagen monomer around the cells and are themselves weak and relatively poorly organised.
Collagen hydrogels by definition contain vast amounts of water (>99%), resulting in limited matrix mechanical properties; much lower than the potential collective strength of the individual collagen fibrils. These matrix properties are known to affect cell behaviour (migration, proliferation and differentiation) and matrix mechanical properties are often improved by processes such as plastic compression (Brown, R et al. Adv. Funct. Mater. 15, 1762-1770 (2005); Hadjipanayi et al, J Tissue Eng Regen Med. (2011) July; 5(7):505-19; WO2006/003442; WO2007/060459) and collagen crosslinking when modelling stiff tissues (such as skin and tendons).
Artificial cross-linking of collagen fibrils to improve the stiffness of the collagen matrix is cytotoxic. This prevents the seeding of interstitial cells at the outset and a lengthy and variable cell seeding stage is required to produce cellular cross-linked collagen biomaterials and constructs.